The long-term objectives of this proposal are to determine the neurohormonal mechanisms that contribute to the ability of the hypothalamic-pituitary-adrenal (HPA) axis to habituate to repeated stress. The goal of the proposed studies is to characterize the role of corticosteroid feedback inhibition in the habituation process. The overall hypothesis of these studies is that corticosteroid feedback inhibition contributes to the ability of the HPA axis to habituate to repeated stress. These studies may have relevance to understanding some of the neuropathology underlying psychiatric disorders, such as clinical depression. For example, depression has been characterized as a stress- related disorder. The HPA axis of many depressed individuals is hyperactive, and many of the physical and behavioral symptoms associated with depression resemble those present during an acute stress state. Thus, depression may be a condition in which the ability to habituate to daily stress is impaired. An understanding of the mechanisms that lead to HPA axis stress habituation may point to factors in the depressed individual that have been altered, thereby preventing adequate stress adaptation. The following 5 specific aims are proposed: Specific Aim 1. To further characterize the extent to which habituation of the HPA axis stress response to repeated restraint stress is dependent on corticosterone. Specific Aim 2. To determine if an enhanced sensitivity of the HPA axis to corticosteroid feedback inhibition contributes to habituation. Specific Aim 3. To determine if delayed corticosteroid feedback inhibition contributes to habituation. Specific Aim 4. To determine if there is an increase in corticosteroid receptor level as a consequence of exposure to repeated restraint stress. Specific Aim 5. To determine if there is an increase in corticosteroid receptor activation by corticosterone as a consequence of exposure to repeated restraint stress. A series of studies are proposed which will use the rat as an in vivo system for studying HPA axis habituation. These studies will utilize a repeated restraint stress regimen that reliably produces habituation of the HPA axis stress response. Characterization of the role of endogenous corticosteroids in the habituation process will be determined in studies in which corticosteroids are systematically manipulated by adrenalectomy and treatment with selective corticosteroid receptor agonists and antagonists Studies will also explore the possibility that a molecular mechanism leading to HPA axis stress habituation is a stress-induced change at the corticosteroid receptor level. Overall, these studies will provide important information about the mechanisms underlying an adaptive response of the HPA axis to repeated stress.